Method of stabilizing organic compounds against oxidation with isoquinoline derivatives

ABSTRACT

Small amounts of isoquinoline derivatives of the formula   RETARD OXIDATION OF FATS, OIL, PLASTICS, RUBBERS, AND OTHER ORGANIC COMPOUNDS BY ATMOSPHERIC OXYGEN, WHEN R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, carboxy or carbo-alkoxy having up to 24 carbon atoms in the alkoxy moiety; R3 is hydrogen, or R2 and R3 jointly constitute a second carbon-tonitrogen bond; R4 is hydrogen or lower alkyl; and R5 is hydrogen, alkali metal, or alkyl having up to 24 carbon atoms.

United States Patent [191 Okumura et al.

[ Nov. 5, 1974 I METHOD OF STABILIZING ORGANIC COMPOUNDS AGAINST OXIDATION WITH ISOQUINOLINE DERIVATIVES [75] Inventors: Shinji Okumura, Tokyo; Shito Takeshita, Kawasaki; Hitoshi Enei, Zushi; Sadayoshi Ninagawa, Yokohama, all of Japan [73] Assignee: Ajinomoto Co., Inc., Tokyo, Japan- [22] Filed: Aug. 17, 1973 [21] Appl. No.: 389,206

[30] Foreign Application Priority Data OTHER PUBLICATIONS Chemical Abstracts, Vol. 75, 1971, 1375546, Bell et 211. Chemical Abstracts, Vol. 77, 1972, 48773w, Daxenbichler et al. Chemical Abstracts, Vol. 76, 1972, 99482n, Brossi et a1.

Primary ExaminerNorman Yudkoff Assistant Examiner-Curtis P. Ribando Attorney, Agent, or Firm-Hans Berman [57] ABSTRACT Small amounts of isoquinoline derivatives of the formula no T c R II cooR 2 retard oxidation of fats, oil, plastics, rubbers, and other organic compounds by atmospheric oxygen, when R is hydrogen or lower alkyl; R is hydrogen,

lower alkyl, carboxy or carbo-alkoxy having up to 24- carbon atoms in the alkoxy moiety; R is hydrogen, or R and R jointly constitute a second carbon-tonitrogen bond; R, is hydrogen or lower alkyl; and R is hydrogen, alkali metal, or alkyl having up to 24 carbon atoms. I

8 Claims, No Drawings METHOD OF STABILIZING ORGANIC COMPOUNDS AGAINST OXIDATION WITH ISOQUINOLINE DERIVATIVES This invention relates to the protection of organic compounds against oxidation by atmospheric oxygen, and particularly to a method of stabilizing such organic compounds against oxidation.

Oils, of animal, vegetal, or mineral origin, fats, rubbers, paraffin wax, synthetic resins, and like organic materials are sensitive to atmospheric oxygen, and deteriorate in storage due to contact with air. It is known to admix small amounts of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid and its salts to oxygen-sensitive organic materials, but there is a need forother antioxidants which are more effective and/or less toxic to humans.

It has now been found that isoquinoline derivatives of the formula R R I Q 2 HO 1 i R3 HO-- COOR are effective antioxidants in amounts so small as to be without significant toxicity to humans. In this formula, R is hydrogen or lower alkyl; R is hydrogen, lower alkyl, carboxy or carbo-alkoxy having up to 24 carbon atoms in the alkoxy moiety; R is hydrogen, or R and R jointly constitute a second carbon-to-nitrogen bond; R is hydrogen or lower alkyl; and R is hydrogen, alkali metal, or alkyl having up to 24 carbon atoms.

The compounds of the invention are water-soluble when R is hydrogen or alkali metal, and are soluble in fats, oils, and like organic compounds when R is alkyl and/or R is carboalkoxy. They also form acid addition salts with hydrochloric, sulfuric, tartaric, succinic, oxalic, p-toluene-sulfonic, pyrrolidonecarboxylic, acetic acid, and a wide variety of other acids having a first dissociation constant at least similar to those of the acids specifically enumerated.

The compounds of the invention are readily prepared by Pictet-Spengler isoquinoline synthesis from 3,4-dihydroxyphenylalanine (DOPA) or salts thereof with suitable carbonyl compounds. The free acids so produced are readily converted to esters in a conventional manner, and the esters, particularly those of alcohols having at least four carbon atoms, effectively inhibit oxidation of fatty and oily triglycerides, such as vegetable oils, animal fats, fish oils, also liquid and solid hydrocarbons including paraffin wax, petroleum fractions including lubricants and motor fuel, the solid polymers of a-monoolefins including polyethylene and polypropylene, transformer oils and the like. Synthetic resins whose oxidation resistance can be improved by small amounts of the compounds of the invention, include linear polyesters and alkyd resins. Natural and synthetic rubbers age more slowly when containing the ous solutions or dispersions of oxygen-sensitive organic compounds.

The application of the isoquinoline derivatives most extensively tested so far is the protection of edible fats and oils, the fatty acids derived from these fats and oils, and the soaps which are alkali metal salts of the fatty acids. The fats and oils which can be stabilized with very small amounts of the isoquinoline derivatives include butter, margerine, soy bean oil, cotton seed oil,

sesame oil, rape seed oil, olive oil, corn oil, peanut oil,

fish oils generally, the fatty acids derived from such fats and oils including oleic acid, linoleic acid, linolenic acid, arachidonic acid, and the soaps which are alkali metal salts of the acids. v The amount of isoquinoline derivative that is intimately mixed with the organic material to-be stabilized varies with the degree of stabilization required, with the presence or absence of other stabilizing materials, the

nature and purity of the material to be protected EXAMPLE 1 I .5 g L-DOPA and 6 g pyruvic acid were dissolved in ml water. The pH of the solution was adjusted to pH 6.0 with ammonium hydroxide, and the solution was kept at37C for 40 hours. It was then acidified to pH 3.0 with hydrochloric acid, and evaporated to about 12 ml in a vacuum at a temperature notexceeding 40C. Upon storage of the residue at 0 to 5C for 24 hours, white crystals formed' When recovered and dried, they weighed 3.2 g and melted at 220C with decomposition.

The product was identified as dicarboxy-6,7-dihydroxy-l ,2,3 ,4-tetrahydroisoquinoline of the formula \Z/ HO NH HO c c coon by nuclear magnetic resonance and mass spectrometer tests. A paper chromatogram gave an'Rf value 'of 0.45 (n-butanol/glacial acetic acid/water 4/1/1 by volume).

EXAMPLE 2 A solution of -2 g 1,-methyl-l,3-dicarboxy-6,7 dihydroxy-l,2,3,4-tetrahydroisoquinoline in 100 ml l-N aqueous ammonium hydroxide was allowed to stand.24 hours, and was then neutralized with hydroisoquinoline derivatives of this invention, and similar chloric acid. Yellow crystals of l-methyl-3-carboxybeneficial effects have been observed in various oxygen-sensitive insecticide compositions and medicines, the water soluble compounds being employed m aque- 6,7-dihyd'roxy-3,4-dihydroisoquinoline of the formula l-methyl-l ,3-

CH EXAMPLE 6 A solution of 5 g a-methyl-3,4-dihydroxyphenylala- HO nine and 5 g sodium pyruvate in 500 ml water was adjusted to pH 1.0 with hydrochloric acid and stored 16 HO ca 5 hours at 315C. It was then adjusted to pH 3.0 with C ammonia, and partly evaporated in a vacuum at less COOH than 40C to crystallize 1,3-dimethyl-1,3-dicarboxy- 6,7-dihydroxy- 1 ,2,3 ,4-tetrahydroisoquinoline.

The compound gave an Rf value of 0.18 in a paper chromatogram developed as in Example 1. precipitated. When recovered, they weighed 0.72 g and melted at 236 with decomposition. EXAMPLE 7 The compound was identified by nuclear molecular 22 g 7 3 4. resonance and mass spectromeler tests and gave an Rf l dihydroisoquinoline prepared as in Example 2 and 38.8 Value of 018 under the condltlons of Example g lauryl alcohol were reacted in the presence of hydro- EXAMPLE 3 gen chloride for hours at 40 50C in a 100 ml three-neck flask equipped with a stirrer, reflux con- A mlxture of g g Sodlum Sumter denser, and thermometer. Unreacted l-methyl-3- g acetone, and 35 ml 28 Percent aqueous ammonia carboxy-6,7-dihydroxy-3,4-dihydroisoquinoline was wjdstheated in a 100 m1 Stainless Steel autoclave with filtered from the esterification mixture, and excessive stlmng at 1 for 50 mmutes- It was Cooled to lauryl alcohol was distilled from the filtrate in a vacroom temperature and evaporated to 10 m] in a uum. The residue was neutralized with aqueous sodium uum. A crystalline precipitate formed in the concen- Carbonate l i trate after overnight storage at 5C, and was found to The crystalline lam-y] ester f 1 3 consist of g y y- 6,7-dihydroxy-3,4-dihydro-isoquinoline was obtained dihydroxy- 1 ,2,3,4-tetrahydroisoquinoline melting at in a yield of 71.4 percent, and melted at 113 115C. 236 240C with decomposition. It was identified as [t was id tifi d by elementary analysis; in the preceding Examples.

The l-methyl-l-ethyl homolog was prepared in an analogous manner when the acetone was replaced by Calculated for rr M r 70.92%0, 906%"; 3-60%N methylethylketonet Found: 70.96 9.17 3.51 v

EXAMPLE 4 The butyl, pentyl and stearyl esters of the same 3- g 20 35 fffifiiZsfi iiftl ii221???$Z$itii$33ft hyde solution were mixed with 100 ml 0.1 N hydrochlob d f th invention were ric acid, and the mixture was adjusted to pH 5.0 with Car oxylsqqumo me compoun s O e ammonium hydroxide solution After 24 hours standing prepared m an analogous qmvepuonal i i at ambient temperature a Crystalline precipitate had up to 24 carbon atoms 1n their alcohol moietles. formed and was recovered. It consisted of 1.4 g 3- 40 carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline EXAMPLE 9 melting at 283C n) which was identi- 9.85 g L-DOPA and 2.6 g acetaldehyde were added fled by elementary analy5i5- to 200 ml water, and the pH of the mixture was adjusted to 0.9 with hydrochloric acid. After 16 hours standing at room temperature, the solution was ad- Calculated for c,,H,,0.N.1/2 H2O 55.04%c, 5.54%H, 6.42%N Justed to P ammonia 3{ Found: 5 5.31 5 .46 6.38 carboxy-6,7-d1hydroxy-l ,2,3 ,4-tetrahydro1soqumolme was precipitated in crystalline form. The recovered 5O crystals weighed 9.1 g. EXAMPLE 5 18.5 g 3,4-Dihydroxyphenylalanine methyl ester hy- EXAMPLE l0 drochloride and 20 mg p-toluenesulfonic acid were diS- Respective batches of soy bean oil were mixed thorsolved in a mixture of 100 m1 dimethylformamide and oughly with 0.02 percent of the antioxidants identified 100 ml 2,2-dimethoxypropane, and the mixture was by R ma num rals as follows; heated 4 hours at 80C under a nitrogen blanket. It was I BI-IT then partly evaporated in a vacuum to form white crys- II 1-Methyl-3-carboxy-6,7-dihydroxy-3,4-dihydrotals of l,1-dimethyl-3-carbomethoxy-6,7-dihydroxyisoquinoline lauryl ester 1,2,3,4-tetrahydroisoquinoline hydrochloride. When III 1-Methyl-3-carboxy-6,7-dihydroxy-3,4- recrystallized from methanolether, the compound dihydroisoquinoline pentyl ester melted at 146C with decomposition. It was identified IV l-Methyl-3-carboxy-6,7-dihydr0Xy-l,2,3,4- by elementary analysis: tetrahydroisoquinoline lauryl ester Calculated for C, -,H,,NO HCl: 54.3% C; 6.3% H; 4.8% N; 12.32% Cl Found: 5406 6.54 4.77 12.32

1 -Methyll ,3-dicarboxy-6,7-dihydroxy- 1 ,2,3,4-

TABLE 1 Anti- Peroxide Value Oxidant 5 hrs. 10 hrs. hrs.

None 3.8 38.2 766.0 I 3.9 17.7 423.4 11 3.1 5.2 27.7 111 3.1 4.8 23.3 IV 3.5 4.0 6.0 V 3.0 4.2 6.3 V1 3.0 19.2 164.8 Vll 3.7 20.8 256.1

EXAMPLE 11 The procedure of Example 10 was repeated with lard instead of soy bean oil, and the results are tabulated in an analogous manner in Table 11.

TABLE II Anti- Peroxide Value Oxidant 5 hrs. 10 hrs. 20 hrs.

None 4.0 12.0 173.0 1 3.8 10.5 43.6 11 2.1 2.3 2.6 111 2.0 2.4 2.7 IV 2.3 2.4 3.0 V 2.1 2.5 2.8 V1 2.8 3.6 11.5 Vll 2.8 4.5 26.3

EXAMPLE 12 Respective batches of soy bean oil were mixed with amounts of 1-methyl-3-carboxy-6,7-dihydroxy-3,4- dihydroisoquinoline lauryl ester (11) varying from 0.0002 to 0.02 percent, and with 0.02 percent BHT (I). The mixtures and a batch of unmixed oil were subjected to the oxidation test described in Example 10 with the results shown in Table Ill.

6 TABLE III Anti- Peroxide Value Oxidant 5 hrs. 10 hrs. 20 hrs.

None 2.8 30.0 605.5 0.02% l 3.9 17.7 423.4 0.0002% 11 3.0 25.4 634.3 0.0004% 11 1.5 24.8 514.3 0.001% 11 3.3 20.8 691.4 0.002% 11 2.3 15.0 599.3 0.006% 11 1.7 6.2 293.1 0.02% 11 2.6 4.9 11.6

What is claimed is:

l. A method of protecting an organic material against oxidation which comprises mixing said material with an isoquinoline derivative of the formula HO- N R wherein R is hydrogen or lower allryl; R is hydrogen,

lower alkyl, carboxy or carbo-alkoxy, said alkoxy having up to 24 carbon atoms; R is hydrogen, or R and R jointly constitutea second carbon-tonitrogen bond; R is hydrogen or lower alkyl; and R is hydrogen, alkali metal or alkyl having up to 24 carbon atoms;

said organic material being an oil, fat or wax of animal,

vegetal, or mineral origin, rubber, or sythetic resin, and sensitive to oxidation by atmospheric oxygen, and the amount of said derivative being sufficient to retard said oxidation.

2. A method as set forth in claim -1, wherein said material is an edible'oil or fat, and the amount of said derivative is between 0.001 and 1.0 percent of the weight of said material.

3. A method as set forth in claim 2, wherein R is alkyl.

4. A method as set forth in claim 3, wherein each of said lower alkyl has up to four carbon atoms.

5. A method as set forth in claim 2, wherein R is methyl, R and R are each hydrogen or jointly constitute said carbon-to-nitrogen bond, R is hydrogen, and R is alkyl.

6. A method as set forth in claim 2, wherein R and R are lower alkyl, R is alkoxy, R is hydrogen, and R is alkyl.

7. A method as set forth in claim 2, wherein R is lower alkyl, R is carboalkoxy, R and R are hydrogen, and R is alkyl.

the method set forth in claim 4. v v 

1. A METHOD OF PROTECTING AN ORGANIC MATERIAL AGAINST OXIDATION WHICH COMPRISES MIXING SAID MATERIAL WITH AN ISOQUINOLINE DERIVATIVE OF THE FORMULA
 2. A method as set forth in claim 1, wherein said material is an edible oil or fat, and the amount of said derivative is between 0.001 and 1.0 percent of the weight of said material.
 3. A method as set forth in claim 2, wherein R5 is alkyl.
 4. A method as set forth in claim 3, wherein each of said lower alkyl has up to four carbon atoms.
 5. A method as set forth in claim 2, wherein R1 is methyl, R2 and R3 are each hydrogen or jointly constitute said carbon-to-nitrogen bond, R4 is hydrogen, and R5 is alkyl.
 6. A method as set forth in claim 2, wherein R1 and R2 are lower alkyl, R3 is alkoxy, R4 is hydrogen, and R5 is alkyl.
 7. A method as set forth in claim 2, wherein R1 is lower alkyl, R2 is carboalkoxy, R3 and R4 are hydrogen, and R5 is alkyl.
 8. An organic material protected against oxidation by the method set forth in claim
 4. 